Host genetic diversity enables Ebola hemorrhagic fever pathogenesis and resistance

Rasmussen, Angela L.; Okumura, Atsushi; Ferris, Martin T.; Green, Richard; Feldmann, Friederike; Kelly, Sara; Scott, Dana; Safronetz, David; Haddock, Elaine; LaCasse, Rachel; Thomas, Matthew; Sova, Pavel; Carter, Victoria S.; Weiss, Jeffrey M.; Miller, Darla R.; Shaw, Ginger D.; Korth, Marcus J.; Heise, Mark T.; Baric, Ralph S.; Villena, Fernando P Pardo Manuel De; Feldmann, Heinz; Katze, Michael G.

doi:10.1126/science.1259595

Cited by 267 publications

(263 citation statements)

References 27 publications

(31 reference statements)

Supporting

Mentioning

244

Contrasting

Unclassified

Order By: Relevance

“…For example, a TIE2-low haplotype suggesting leak-prone blood vessels may guide clinicians to use fluid-conservative strategies to minimize ARDS risk. Because the Tie2 pathway has been linked to an even broader array of infections than studied here, such as Ebola and Hantavirus (40,41), the impact of genetic determinants for Tie2 protein abundance and function merits further investigation. More broadly, genetic biomarkers of vascular leak risk could catalyze drug discovery for therapies targeting the vasculature by facilitating prognostic enrichment in clinical trials.…”

Section: Discussionmentioning

confidence: 99%

Gene control of tyrosine kinase TIE2 and vascular manifestations of infections

Ghosh

David

Zhang

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Ligands of the endothelial-enriched tunica interna endothelial cell kinase 2 (Tie2) are markedly imbalanced in severe infections associated with vascular leakage, yet regulation of the receptor itself has been understudied in this context. Here, we show that TIE2 gene expression may constitute a novel vascular barrier control mechanism in diverse infections. Tie2 expression declined rapidly in wide-ranging models of leak-associated infections, including anthrax, influenza, malaria, and sepsis. Forced Tie2 suppression sufficed to attenuate barrier function and sensitize endothelium to permeability mediators. Rapid reduction of pulmonary Tie2 in otherwise healthy animals attenuated downstream kinase signaling to the barrier effector vascular endothelial (VE)-cadherin and induced vascular leakage. Compared with wild-type littermates, mice possessing one allele of Tie2 suffered more severe vascular leakage and higher mortality in two different sepsis models. Common genetic variants that influence TIE2 expression were then sought in the HapMap3 cohort. Remarkably, each of the three strongest predicted cis-acting SNPs in HapMap3 was also associated with the risk of acute respiratory distress syndrome (ARDS) in an intensive care unit cohort of 1,614 subjects. The haplotype associated with the highest TIE2 expression conferred a 28% reduction in the risk of ARDS independent of other major clinical variables, including disease severity. In contrast, the most common haplotype was associated with both the lowest TIE2 expression and 31% higher ARDS risk. Together, the results implicate common genetic variation at the TIE2 locus as a determinant of vascular leak-related clinical outcomes from common infections, suggesting new tools to identify individuals at unusual risk for deleterious complications of infection.Tie2 | endothelium | infection | angiopoietin | permeability

show abstract

Section: Discussionmentioning

confidence: 99%

Gene control of tyrosine kinase TIE2 and vascular manifestations of infections

Ghosh

David

Zhang

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…Reduced Tie1 RNA is linked to susceptibility to Ebola virus-induced hemorrhagic fever and vascular leakage in mice (78), providing evidence that loss of Tie1 is associated with disease pathogenesis and contributes to reduced vascular stability.…”

Section: Requirement Of Tie1 For Ang2 Agonist Activity In Vivomentioning

confidence: 99%

Tie1 controls angiopoietin function in vascular remodeling and inflammation

Korhonen

Lampinen

Giri³

et al. 2016

Journal of Clinical Investigation

195

279

View full text Add to dashboard Cite

The angiopoietin/Tie (ANG/Tie) receptor system controls developmental and tumor angiogenesis, inflammatory vascular remodeling, and vessel leakage. ANG1 is a Tie2 agonist that promotes vascular stabilization in inflammation and sepsis, whereas ANG2 is a context-dependent Tie2 agonist or antagonist. A limited understanding of ANG signaling mechanisms and the orphan receptor Tie1 has hindered development of ANG/Tie-targeted therapeutics. Here, we determined that both ANG1 and ANG2 binding to Tie2 increases Tie1-Tie2 interactions in a β 1 integrin-dependent manner and that Tie1 regulates ANG-induced Tie2 trafficking in endothelial cells. Endothelial Tie1 was essential for the agonist activity of ANG1 and autocrine ANG2. Deletion of endothelial Tie1 in mice reduced Tie2 phosphorylation and downstream Akt activation, increased FOXO1 nuclear localization and transcriptional activation, and prevented ANG1-and ANG2-induced capillary-to-venous remodeling. However, in acute endotoxemia, the Tie1 ectodomain that is responsible for interaction with Tie2 was rapidly cleaved, ANG1 agonist activity was decreased, and autocrine ANG2 agonist activity was lost, which led to suppression of Tie2 signaling. Tie1 cleavage also occurred in patients with hantavirus infection. These results support a model in which Tie1 directly interacts with Tie2 to promote ANG-induced vascular responses under noninflammatory conditions, whereas in inflammation, Tie1 cleavage contributes to loss of ANG2 agonist activity and vascular stability. The Journal of Clinical Investigation R E S E A R C H A R T I C L E3 4 9 6 jci.org Volume 126 Number 9 September 2016We found that angiopoietins promoted a direct interaction of Tie1 and Tie2 and that this interaction was regulated by integrin β 1 . ANG1-and ANG2-induced Tie2 activation and vascular remodeling were reduced or absent in mice where Tie1 was deleted in vascular endothelial cells. Tie1 deletion also attenuated ANG1-induced Akt activation and nuclear exclusion of FOXO1. We found that Tie1 was suppressed via ectodomain cleavage during acute inflammation and that this was associated with reduced agonistic activity of ANG2 and decreased Tie2 signaling. These results indicate that the agonist action of ANG2 is attenuated in inflammation and that Tie1 is an essential component of the angiopoietin signaling system that has potential for therapeutic targeting in disease. ResultsAngiopoietins induce direct interaction of Tie1 and Tie2. To investigate the dynamics of the Tie receptors in angiopoietin signaling, we transfected HUVECs with retroviral vectors expressing full-length (FL) Tie1 and Tie2, tagged on the C terminus with mCherry and GFP, respectively. Stimulation of FL-Tie2-GFP and FL-Tie1-mCherry expressing endothelial cells with COMP-Ang1 (CAng1) (49) or with recombinant human ANG2 induced colocalization of Tie1 and Tie2 in endothelial cell-cell junctions ( Figure 1A and Supplemental Video 1; supplemental material available online with this article; doi:10.1172/JCI84923DS1) (44,45,50). To investigat...

show abstract

“…Specialized statistical methods have been developed to analyze this unique population (Gong and Zou 2012). A striking example of the power of CC-RIX strains is illustrated by their markedly different response to infection by a mouse-adapted strain of the Ebola virus, thus providing among the first and best mouse models for studying Ebola infection, and in particular the associated hemorrhagic fever (Rasmussen et al 2014).…”

Section: Collaborative Cross (Cc)mentioning

confidence: 99%

“…The CC was used to show that resistance to influenza A virus infection was largely due to variants in Mx1 (Ferris et al 2013). The CC-RIX mice were used to identify an association between Tek and susceptibility to Ebola infection (Rasmussen et al 2014). Tek expression was decreased in Ebola susceptible mice relative to Ebola resistant mice and was therefore hypothesized to influence Ebola susceptibility by regulating vascular integrity (Rasmussen et al 2014).…”

Section: Identified Qtlsmentioning

confidence: 99%

“…The CC-RIX mice were used to identify an association between Tek and susceptibility to Ebola infection (Rasmussen et al 2014). Tek expression was decreased in Ebola susceptible mice relative to Ebola resistant mice and was therefore hypothesized to influence Ebola susceptibility by regulating vascular integrity (Rasmussen et al 2014). OS mice were used to fine-map a QTL for anxiety that led to the identification that Rgs2 regulates anxiety behavior (Yalcin et al 2004).…”

Section: Identified Qtlsmentioning

confidence: 99%

See 1 more Smart Citation

Contrasting genetic architectures in different mouse reference populations used for studying complex traits

Buchner

Nadeau

2015

Genome Res.

View full text Add to dashboard Cite

Quantitative trait loci (QTLs) are being used to study genetic networks, protein functions, and systems properties that underlie phenotypic variation and disease risk in humans, model organisms, agricultural species, and natural populations. The challenges are many, beginning with the seemingly simple tasks of mapping QTLs and identifying their underlying genetic determinants. Various specialized resources have been developed to study complex traits in many model organisms. In the mouse, remarkably different pictures of genetic architectures are emerging. Chromosome Substitution Strains (CSSs) reveal many QTLs, large phenotypic effects, pervasive epistasis, and readily identified genetic variants. In contrast, other resources as well as genome-wide association studies (GWAS) in humans and other species reveal genetic architectures dominated with a relatively modest number of QTLs that have small individual and combined phenotypic effects. These contrasting architectures are the result of intrinsic differences in the study designs underlying different resources. The CSSs examine contextdependent phenotypic effects independently among individual genotypes, whereas with GWAS and other mouse resources, the average effect of each QTL is assessed among many individuals with heterogeneous genetic backgrounds. We argue that variation of genetic architectures among individuals is as important as population averages. Each of these important resources has particular merits and specific applications for these individual and population perspectives. Collectively, these resources together with high-throughput genotyping, sequencing and genetic engineering technologies, and information repositories highlight the power of the mouse for genetic, functional, and systems studies of complex traits and disease models.

show abstract

Host genetic diversity enables Ebola hemorrhagic fever pathogenesis and resistance

Cited by 267 publications

References 27 publications

Gene control of tyrosine kinase TIE2 and vascular manifestations of infections

Gene control of tyrosine kinase TIE2 and vascular manifestations of infections

Tie1 controls angiopoietin function in vascular remodeling and inflammation

Contrasting genetic architectures in different mouse reference populations used for studying complex traits

Contact Info

Product

Resources

About